Chronic social stress in adolescence influenced both amphetamine conditioned place preference and locomotor sensitization.

We previously reported that chronic social stress (SS) in adolescence, but not in adulthood, increased the locomotor-activating effects of nicotine in females, and not males, when tested in adulthood. However, SS rats had decreased locomotor response to nicotine when tested in adolescence. Here, we investigated age-related changes in the effects of SS on both conditioned place preference (CPP) and locomotor sensitization to amphetamine. In the CPP experiment, SS females tested in adolescence had increased preference for the 1.0 mg/kg dose of amphetamine, whereas SS rats of both sexes showed a decrease in CPP for the 0.5 mg/kg dose when tested as adults. Irrespective of time of testing, SS males and females had enhanced locomotor sensitization compared to controls. Thus, adolescent SS produced both immediate and enduring effects on behavioral responses to amphetamine, likely by altering the development of the mesocorticolimbic dopamine system, which holds implications for vulnerability to addiction.

Transsphenoidal surgery for acromegaly in wales: results based on stringent criteria of remission.

We retrospectively analyzed 90 patients who underwent transsphenoidal surgery (performed by three surgeons) in our center as initial therapy for acromegaly. We used a combination of modern, evidence-based remission criteria including mean day curve GH less than 2.5 micro g/liter (5 mU/liter), a nadir GH less than 1.0 micro g/liter (2 mU/liter) after an oral glucose tolerance test, and normal age-related IGF-I levels (where available). Fifty-seven of 90 (63%) patients remained in remission after surgery. Seventy-nine percent of patients with microadenomas but only 56% of patients with macroadenomas achieved remission (P < 0.001). Eighty-six percent of patients with preoperative GH levels below 10 micro g/liter (day profile or after oral glucose tolerance test) went into remission, compared with 51% of patients with GH levels above 25 micro g/liter at diagnosis (P < 0.002). The remission rate was also related to the period of surgery that was significantly higher in 1998-2001 (76%; P < 0.05) compared with 1990-1997 (54%) and 1980-1989 (63%). There were no recurrences or perioperative deaths. Meningitis occurred in 3% of patients, cerebrospinal fluid rhinorrhea in 7%, and permanent diabetes insipidus in 15%. The proportion of patients who developed new anterior pituitary hormone deficiencies and panhypopituitarism was significantly less in the period 1998-2001 (P < 0.001) when compared with the periods from 1990-1997 and 1980-1989. Transsphenoidal surgery is a safe and effective treatment for acromegaly, and our results compare favorably with those from published series. The presence of an intrasellar lesion and low preoperative GH levels is a good predictor of remission in the long term, but historically in our center this can only be achieved in a significant proportion of patients at the expense of some degree of hypopituitarism. However, surgical outcome in our center, including a reduced frequency of hypopituitarism, has improved significantly over time, coincident with the arrival of a dedicated pituitary neurosurgeon and the use of selective adenomectomy as the preferred surgical approach wherever possible.

Conformation of sarafotoxin-6b in aqueous solution determined by NMR spectroscopy and distance geometry.

The solution structure of sarafotoxin-6b in water has been determined using high-resolution NMR spectroscopy. 127 proton-proton distance measurements and three phi dihedral angle constraints derived from NMR spectra were used to calculate the solution structure using a combination of distance geometry and restrained molecular dynamics. The major structural feature of the resulting family of five structures was a right-handed alpha-helix extending from K9 to Q17. In contrast, the C-terminal region of the peptide appears not to adopt a preferred conformation in aqueous solution. The present structure is compared with those previously determined for endothelin peptides in non-aqueous solvents.

Glucose inhibition of human fibroblast proliferation and response to growth factors is prevented by inhibitors of aldose reductase.

Diabetes mellitus is associated with premature senescence of cultured dermal fibroblasts. The present study investigated the effect of elevated glucose concentrations on cultured human fibroblasts from normal donors. Mean population doubling times, population doublings until senescence, saturation density at confluence (cells/cm2), tritiated thymidine incorporation, and response to platelet-derived growth factor (PDGF) were inhibited with the increasing glucose concentrations (11.0, 22, 44, or 55 mM glucose) (P less than 0.05). Replicative life span was markedly diminished by multiple passages in high glucose medium (5.5 mM glucose: 62.4 +/- 7.9 population doublings; 22 mM glucose: 22.8 +/- 3.4 population doublings: P less than 0.05). Aldose reductase activity was present in the cultured fibroblasts (3.9 +/- 0.5 nmol/min per mg protein), and inhibitors of aldose reductase, including sorbinil (10(-4) M--10(-6) M) and tolrestat (10(-6) M--10(-8) M), completely prevented glucose-mediated inhibition of fibroblast proliferation, restored the response to PDGF, and allowed a normal replicative life span. Myo-inositol (11 microM--5.5 mM) also reversed the adverse effects of glucose. These in vitro data demonstrate that elevated concentrations of glucose inhibit cell growth and promote premature senescence, effects which can be prevented with inhibitors of aldose reductase or supplemental myo-inositol. These aldose reductase-related effects may explain the impaired growth and premature senescence of cultured connective tissue from diabetic patients.

Early viral brain invasion in iatrogenic human immunodeficiency virus infection.

We report a 68-year-old man who received an IV inoculation of WBCs for an indium radionuclide scan containing 600 to 700 tissue culture infectious doses of human immunodeficiency virus type 1 (HIV-1) from an HIV-1-infected individual. The recipient immediately received zidovudine, then was switched to dideoxyinosine and interferon-alpha, but died of hepatorenal syndrome and hepatic encephalopathy 15 days later. HIV-1 cultures were positive from the recipient's blood on day 14 but not days 0, 1, and 8. At autopsy, cultures of parietal lobe isolated HIV-1. HIV-1 nucleic acid was present in several brain areas, but not in several other organs, by two independent laboratories using the polymerase chain reaction. The brain showed mild perivascular cuffing and a mild lymphocytic meningitis, but there was no evidence of glial nodules, giant cells, or white matter abnormalities. HIV-1 pg41 viral antigen was seen by immunoperoxidase staining in rare infiltrating cells within perivascular and subpial spaces. Thus, HIV-1 was isolated from brain 15 days after mistaken HIV-1 inoculation and 1 day after virus was first recovered from blood.

HIV-1 infection despite immediate combination antiviral therapy after infusion of contaminated white cells.

We present a sixth human case in which primary human immunodeficiency virus (HIV-1) infection occurred, despite antiretroviral prophylaxis, after accidental inoculation of infected blood. In the prior five instances, variables such as large virus dose, late administration of antivirals, viral resistance to zidovudine, and pre-existent immunosuppression, may have played a role in the treatment failure. In this case, high-dosage oral zidovudine was given within minutes of the accident and replaced 2 1/2 days later with interferon alpha and dideoxyinosine (ddl). Despite aggressive treatment, HIV-1 infection was demonstrated in blood, spleen, and brain tissue at autopsy 16 days later. Of the tissues studied, detection of HIV-1 was most prominent in the spleen. Double-label immunocytochemistry confirmed the morphologic impression that while some of the infected spleen cells were CD3-positive T cells, the majority were macrophages. Thus, current single or dual (zidovudine, ddl-interferon) therapies for accidental HIV-1 inoculation may not be effective in preventing early infection. Further trials in animals appear warranted to evaluate protection by other strategies, such as passive immunity or combinations of agents that penetrate the brain and attack HIV-1 viral replication at differing sites.

Synthesis and anti-HIV activity of 1,1'-dideoxygossypol and related compounds.

1,1'-Dideoxygossypol (DDG), 1,1'-dideoxygossylic acid (DDGA), 8-deoxyhemigossypol (DHG), and 8-deoxyhemigossylic acid (DHGA) were synthesized and tested for their ability to inhibit the replication of HIV in vitro. The EC50 for DDGA was < 1 microM, and its threshold cytotoxicity was approximately 20 microM. DDG was less effective than DDGA against HIV and showed considerable toxicity at 5 microM. DHGA was ineffective against HIV and had very low cytotoxicity. DHG showed some anti-HIV activity, but the threshold cytotoxicity was 5 microM. The dissociation constants for the binding of the four compounds to human serum albumin were determined by fluorescence quenching titrations, and all four were found to have much lower affinities for albumin than the parent compound gossypol.

Oral oseltamivir treatment of influenza in children.

BACKGROUND: Oral oseltamivir administration is effective treatment for influenza in adults. This study was conducted to determine the efficacy, safety and tolerability of oseltamivir in children with influenza. METHODS: In this randomized, double blind, placebo-controlled study, children 1 through 12 years with fever [> or =100 degrees F (> or =38 degrees C)] and a history of cough or coryza <48 h duration received oseltamivir 2 mg/kg/dose or placebo twice daily for 5 days. The primary efficacy endpoint was the time to resolution of illness including mild/absent cough and coryza mild/absent, return to normal activity and euthermia. RESULTS: Of 695 enrolled children 452 (65%) had influenza (placebo, n = 235; oseltamivir, n = 217). Among infected children the median duration of illness was reduced by 36 h (26%) in oseltamivir compared with placebo recipients (101 h; 95% confidence interval, 89 to 118 vs. 137 h; 95% confidence interval, 125 to 150; P < 0.0001). Oseltamivir treatment also reduced cough, coryza and duration of fever. New diagnoses of otitis media were reduced by 44% (12% vs. 21%). The incidence of physician-prescribed antibiotics was significantly lower in influenza-infected oseltamivir (68 of 217, 31%) than placebo (97 of 235, 41%; P = 0.03) recipients. Oseltamivir therapy was generally well-tolerated, although associated with an excess frequency of emesis (5.8%). Discontinuation because of adverse events was low in both groups (1.8% with oseltamivir vs. 1.1% with placebo). Oseltamivir treatment did not affect the influenza-specific antibody response. CONCLUSIONS: Oral oseltamivir administration is an efficacious and well-tolerated therapy for influenza in children when given within 48 h of onset of illness.

Sarcoidosis of the upper respiratory tract and its relation to lupus pernio.

The authors present a personally studied series of 32 patients with sarcoidosis affecting the upper respiratory tract and nose. Twenty-five of these patients had lupus pernio (LP), which in 8 instances was accompanied by sarcoidosis of the upper respiratory tract (SURT). The 7 other patients had SURT (mucosal disease) without LP. There was a female to male ratio of 7:1. SURT presented mainly in the third decade, whereas LP presented mainly in the fourth and fifth. Despite this, SURT was as much a chronic manifestation of sarcoidosis as LP. Five of 11 patients (45%) presenting with SURT progressed to LP within 2 yr. Overall 26 patients (81%) had intrathoracic sarcoidosis, 19 patients (59%) had skin lesions other than LP, 10 patients (31%) had bone sarcoidosis, 7 patients (22%) had ocular lesions, and 6 patients (19%) had peripheral lymphadenopathy. The Kveim-Siltzbach skin-test was positive in 12 of 12 patients with SURT, making it a useful aid in the differential diagnosis of sarcoid granulomas in the nose. Two patients had nasal perforations, both of which followed a submucous resection.

Role of extracellular [Ca2+] in fatigue of isolated mammalian skeletal muscle.

The possible role of altered extracellular Ca2+ concentration ([Ca2+]o) in skeletal muscle fatigue was tested on isolated slow-twitch soleus and fast-twitch extensor digitorum longus muscles of the mouse. The following findings were made. 1) A change from the control solution (1.3 mM [Ca2+]o) to 10 mM [Ca2+]o, or to nominally Ca2+-free solutions, had little effect on tetanic force in nonfatigued muscle. 2) Almost complete restoration of tetanic force was induced by 10 mM [Ca2+]o in severely K+-depressed muscle (extracellular K+ concentration of 10-12 mM). This effect was attributed to a 5-mV reversal of the K+-induced depolarization and subsequent restoration of ability to generate action potentials (inferred by using the twitch force-stimulation strength relationship). 3) Tetanic force depressed by lowered extracellular Na+ concentration (40 mM) was further reduced with 10 mM [Ca2+]o. 4) Tetanic force loss at elevated extracellular K+ concentration (8 mM) and lowered extracellular Na+ concentration (100 mM) was partially reversed with 10 mM [Ca2+]o or markedly exacerbated with low [Ca2+]o. 5) Fatigue induced by using repeated tetani in soleus was attenuated at 10 mM [Ca2+]o (due to increased resting and evoked forces) and exacerbated at low [Ca2+]o. These combined results suggest, first, that raised [Ca2+]o protects against fatigue rather than inducing it and, second, that a considerable depletion of [Ca2+]o in the transverse tubules may contribute to fatigue.

Axonal transport and distribution of cyclophilin A in chicken neurones.

In the course of pulse-label studies on the axonal transport of the small, basic, actin-binding proteins--actin depolymerizing factor, cofilin and profilin--in chicken motor neurones, we observed a heavily labelled protein of M(r) 18 kDa and pI 8.2 on fluorographs of two-dimensional polyacrylamide gels. On the basis of its M(r), pI and amino acid composition, we tentatively identified it by database searching as cyclophilin A and subsequently confirmed its identity by immunostaining. Like actin and its associated proteins, cyclophilin A was transported in slow component b of axonal transport, but unlike these proteins, cyclophilin A did not copurify with actin on DNase I. It was not found amongst labelled proteins transported by fast axonal transported by fast axonal transport. Immunostaining of chicken dorsal root ganglion cells revealed that it accumulated in neurites at points of branching, varicosities and growth cones. Our results raise the possibility that cyclophilin A is important in maintaining the native folding of actin and associated proteins during transit in axons and assembly in growth cones.

Evidence for a neural inhibitory factor which downregulates fetal-type acetylcholine receptor expression in skeletal muscle cell lines.

Nerve-evoked muscle depolarisation plays an important role in the downregulation of extrasynaptic AChRs which accompanies the increase in synaptic AChR expression at the neuromuscular junction during embryonic development. However, additional mechanisms may be involved in the AChR downregulation. This study provides evidence for a neurotrophic factor present in adult and embryonic chick neural extracts which downregulates fetal-type AChR density independently of depolarisation. Treatment of skeletal muscle cell lines with crude neural extracts decreased AChR density up to 50%, as measured by changes in 125I-alpha-bungarotoxin binding levels. Decreases in membrane-bound AChR density were accompanied by a decrease in the size of the intracellular AChR pool; RT-PCR analysis demonstrated that extract treatment also induced a decrease in gamma-subunit mRNA expression. These studies demonstrate that crude neural extracts contain a factor which may account for the activity-independent regulatory mechanism previously proposed to operate in concert with activity-dependent mechanisms to downregulate fetal-type AChR expression.

Distribution of osmosensitive cells in the preoptic and adjacent regions of cat brains.

The response of neurons in the preoptic and adjacent regions of the brain to intracarotid injection of hyperosmotic solutions was studied in 22 anesthetized cats. NaCl (0.5 M) caused a brisk acceleration of frequency lasting over 100 s in 120 of 207 units (58%). Glucose (2 M) and sucrose (2 M) had similar but smaller effects, and urea (2 M) was ineffective. Responding units were found in all parts of the preoptic region, the diagonal band of Broca (vertical limb), the lateral septal nucleus, nucleus accumbens and anterior hypothalamus.

Effects of electrical stimulation and tetrodotoxin paralysis on antigenic properties of acetylcholine receptors in rat skeletal muscle.

To examine the role of muscle activity in the expression of fetal- and adult-type acetylcholine receptors (AChRs), we studied the effects of muscle stimulation in cell culture and of tetrodotoxin (TTX)-induced paralysis and denervation in adult rat muscles. The AChR content of these muscles was determined using [125I]alpha-bungarotoxin and the proportion of fetal-type receptors was estimated using a radioimmunoprecipitation assay with a myasthenic serum that was highly specific for fetal-type receptors. We found that both stimulated, aneural muscle cells in vitro and inactive muscles in vivo produced predominantly fetal-type AChRs. However the TTX-paralysed muscles had a lower proportion of fetal-type receptors than the denervated muscles. We conclude that neither muscle activity nor innervation alone, but a combination of both, is required for full regulation of AChR antigenicity.

Response to beta-blockers in maternal and fetal rat hearts in vitro.

The effects of beta-blockers on maternal and fetal heart rates have been assessed by comparing isoprenaline concentration-heart rate relationships of hearts isolated from pregnant rats. The normal and maximal heart rates obtained for the maternal and fetal hearts were similar to published data. A slightly but significantly higher concentration of isoprenaline was required to produce 50% of the maximal response of fetal hearts than maternal hearts, suggesting that fetal hearts were less sensitive to isoprenaline than the maternal hearts. The beta-blockers used (propranolol, labetalol, metoprolol and atenolol) all showed a lower affinity to the beta-receptors of fetal hearts than those of maternal hearts, as indicated by significant differences in the pA2 values. Given the similar effects of the beta-blockers in the maternal and fetal hearts it is concluded that pharmacokinetic considerations and beta-blocker selectivity should be used as the basis of choice when treating maternal hypertension during pregnancy.

Voice changes in acromegaly.

The fundamental frequency of 14 patients undergoing hypophysectomy was studied. Eight patients had acromegaly, 3 had a prolactinoma, and 3 had nonfunctioning adenomas. The fundamental frequency of 22 normal, healthy volunteers was measured for comparison. In addition, the external size of the larynx of all patients and volunteers was measured and a relationship between external laryngeal size and the mean fundamental frequency was identified in the volunteers. The mean fundamental frequency in patients with acromegaly was significantly lower than the other 6 patients undergoing hypophysectomy and, in addition, was also lower than the 22 normal volunteers. Postoperatively the fundamental frequency of the acromegalic patients increased rapidly to within the expected normal range. Patients with acromegaly have a lowered fundamental frequency which is most likely due to altered vocal cord mass and elasticity, which is a reversible change. Patients with acromegaly can expect a rapid and complete return of normal fundamental frequency within 2 weeks of surgery to remove the pituitary adenoma.

The pathophysiology of otitic hydrocephalus.

The pathophysiology of otitic hydrocephalus remains controversial. It has been argued that involvement of the superior sagittal sinus, by, at least, a mural thrombus is a necessary component of this disease. We present a case of otitic hydrocephalus where on magnetic resonance imaging (MRI) normal luminal and mural flow within the superior sagittal sinus is demonstrated. The presence of thrombus in the lateral venous sinus alone appears sufficient in this case to impede venous drainage of the intracranial contents into the neck and produce a rise in the cerebral venous pressure and a subsequent increase in the CSF pressure. The presence of a superior sagittal sinus mural thrombus is not required.

'Ceruminoma'--a defunct diagnosis.

The clinical and pathological features of glandular tumours of the external auditory meatus are presented. Their heterogenous clinical and pathological features make the collective term 'ceruminoma' ambiguous and misleading. The spectrum of pathological behaviour and histological features demonstrated by these interesting tumours necessitate a broader classification system. In our hospital 32 patients presented with tumours of the external auditory meatus over a 30-year period, of which seven were glandular in origin. A review of the histology of these glandular tumours enabled us to reclassify them as adenoma, cylindroma, adenoid cystic carcinoma or ceruminous adenocarcinoma. Together with the less common mucoepidermoid carcinoma and pleomorphic adenoma this subdivision forms a basis for a more meaningful classification system with prognostic and therapeutic implications specific to each tumour type. The term 'ceruminoma' should no longer be used unqualified.

Prediagnostic malakoplakia presenting as a chronic inflammatory mass in the soft tissues of the neck.

Malakoplakia presenting in the head and neck is very rare. We present a case of an inflammatory mass in the neck, clinically mimicking actinomycosis in a 67-year-old man. Repeated culture of E. coli and histological and electron microscopic examination of biopsy material showed an infiltration of granular macrophages and intracellular gram negative bacilli, but no classical Michaelis-Gutmann bodies. The clinical and pathological findings and criteria for the diagnosis of malakoplakia are discussed.

Introduction of a thermal response to the DSTL PADC personal neutron dosemeter.

The response of the Defence Science and Technology Laboratory (DSTL) PADC personal neutron dosemeter is strongly dependent upon neutron energy, with a range of 300-500 tracks per cm2 per mSv for energies between 1 and 5 MeV. Below 1 MeV the response drops off sharply. This lack of sensitivity is undesirable when the dosemeter is employed with the softened fission spectra encountered in the workplace. In order to incorporate a thermal response, a polypropylene converter doped with LiF has been placed directly in front of the PADC elements. Tritons produced in the thermal neutron reaction 6Li (n,t)alpha at 2.7 MeV will then penetrate the PADC, leaving a trail of damage. The reaction rate within the converter has been calculated using MCNP for thermal neutrons and a range of higher energies, while transport of the tritons is modelled using the SRIM/TRIM package to determine the resultant track density and depth distribution. The modelling and experimental work have demonstrated that a concentration of 0.2% natural lithium by weight results in a track density in a thermal field comparable with that produced per unit personal dose equivalent by neutrons greater than 1 MeV in the standard dosemeter. Additional MCNP modelling has demonstrated that the dosemeters' albedo response to intermediate energy neutrons can be enhanced considerably by placing a boron-doped shield in front of the converter and increasing its lithium concentration.